Introduction

Uses for Bortezomib

Previously Untreated Multiple Myeloma

In combination with melphalan and prednisone for previously untreated multiple myeloma.12024

Relapsed Multiple Myeloma

Treatment of multiple myeloma in patients who have received at least 1 prior therapy.137

Retreatment of multiple myeloma in patients who previously responded to bortezomib-based therapy and relapsed ≥6 months following therapy.129

More effective than high-dose dexamethasone in achieving complete or partial response, prolonging time to disease progression, and improving survival in patients with progressive multiple myeloma who had received 1–3 prior chemotherapy regimens.18

Use with dexamethasone†10012 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†.10032 Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.10032

Use with thalidomide and dexamethasone†10013100141001610027 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†;10033 however, use of a modified bortezomib-thalidomide-dexamethasone† regimen using reduced bortezomib and thalidomide dosages10015 is not fully established because of unclear risk/benefit and/or inadequate experience.10033 Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.10033

Use with doxorubicin (or pegylated liposomal doxorubicin) and dexamethasone†100231002410025 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†;10034 however, in the absence of longer follow-up data, use of a modified bortezomib-pegylated liposomal doxorubicin-dexamethasone† regimen using reduced bortezomib and pegylated liposomal doxorubicin dosages10026 is not fully established because of unclear risk/benefit and/or inadequate experience.10034 Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.10034

Use with cyclophosphamide and dexamethasone†1001910021100221002810029 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients†.10035 Consider cytogenetic features, performance status, preexisting conditions (e.g., peripheral neuropathy), and tolerability when selecting a combination chemotherapy regimen.10035

Antiviral Prophylaxis

Administration

For solution and drug compatibility information, see Compatibility under Stability.

Dispensing and Administration Precautions

Administer only by IV or sub-Q injection (see Contraindications under Cautions); sub-Q injection may be considered in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.1

When dispensing, label syringe holding the individual dose with sticker provided by the manufacturer indicating route of administration.1

Rate of Administration

Sub-Q Administration

Give new injections ≥1 inch from previous injection site; do not give injections into areas where skin is tender, erythematous, bruised, or indurated.1

Reconstitution

To reconstitute, add 1.4 mL of 0.9% sodium chloride injection to vial containing 3.5 mg of bortezomib to yield final concentration of 2.5 mg/mL.1 If local injection site reactions occur, the manufacturer recommends reconstituting the drug to a final concentration of 1 mg/mL or considering IV administration.1

Administer within 8 hours after reconstitution.1 (See Storage under Stability.)

Dosage

Consult specialized references and published protocols for dosage (including dosage adjustments in special populations), method of administration, and administration sequence of drugs in combination regimens.1

Use caution when calculating dose and respective volume of bortezomib to prevent overdosage; drug quantity contained in one 3.5-mg vial may exceed usual single dose required.1

If prolonged grade 4 neutropenia or thrombocytopenia or thrombocytopenia with bleeding observed in previous VMP cycle

Consider reduction of melphalan dose by 25% in next cycle

Platelet count ≤30,000/mm3 or ANC ≤750/mm3 on a day when bortezomib is to be administered (other than on day 1)

Withhold bortezomib dose

If several doses of bortezomib were withheld in consecutive cycles because of toxicity

Reduce bortezomib dose by one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2 or a dose of 1 mg/m2 reduced to 0.7 mg/m2)

Grade ≥3 nonhematologic toxicity (excluding neuropathy)

Withhold bortezomib until toxicity resolves to grade 1 or baseline; may then reinitiate bortezomib with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2)

Bortezomib-related neuropathic pain and/or peripheral neuropathy

See Table 2 under Dosage Modification for Peripheral Neuropathy in Relapsed Multiple Myeloma

Retreatment following prior response to bortezomib therapy and disease progression ≥6 months following last therapy: Administer last tolerated dose of bortezomib IV or sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21) for up to 8 cycles.1 May be administered with or without dexamethasone.1

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 during cycles 1 and 2 and then on days 1–4 during cycles 3 and 4.1000210012 Treatment cycles repeated every 21 days for 4 cycles.1000210012

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with doxorubicin hydrochloride 9 mg/m2 IV per day on days 1–4 and dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 of each 28-day cycle for 3 cycles.10023

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 and dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 of each 28-day cycle for 4 cycles.10019

Bortezomib 1.5 mg/m2 IV once weekly (days 1, 8, 15, and 22) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 of each 28-day cycle for 4 cycles, with dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 during cycles 1 and 2 and then once weekly during cycles 3 and 4.10021

If response is first observed at cycle 6, manufacturer recommends 2 additional cycles.1

At least 72 hours should elapse between consecutive doses of bortezomib.1

Dosage Modification for Toxicity for VR-CAP Regimen

IV

Before administering cycles 2–6 of VR-CAP, platelet counts should be ≥100,000/mm3, ANC should be ≥1500/mm3, hemoglobin concentration should be ≥8 g/dL, and nonhematologic toxicities should have resolved to grade 1 or baseline.1

If grade ≥3 neutropenia or platelet count ≤25,000/mm3 on a day when bortezomib is to be administered (other than on day 1)

Withhold bortezomib dose for up to 2 weeks until ANC ≥750/mm3 and platelet counts ≥25,000/mm3; may then reinitiate bortezomib with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2); if toxicity has not resolved, discontinue bortezomib therapy

Grade ≥3 nonhematologic toxicity (excluding neuropathy) on a day when bortezomib is to be administered (other than on day 1)

Withhold bortezomib until toxicity resolves to grade ≤2; may then reinitiate bortezomib with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2)

Administer the adjusted regimen for 2 weeks, followed by a 10-day rest period.6

Special Populations

Hepatic Impairment

Moderate (i.e., bilirubin concentrations >1.5–3 times ULN with any AST concentrations) or severe (i.e., bilirubin concentrations >3 times ULN with any AST concentrations) hepatic impairment: Reduce bortezomib dose during first cycle to 0.7 mg/m2.1 Based on patient tolerance, either increase dosage in subsequent cycles to 1 mg/m2 or further reduce to 0.5 mg/m2.1

Contraindications

Warnings/Precautions

Peripheral Neuropathy

Risk of severe (grade 3 or greater) new-onset peripheral neuropathy or exacerbation of preexisting peripheral neuropathy.1 Occurs predominantly as peripheral sensory neuropathy, but severe peripheral motor neuropathy also reported.1 Manifestations improved or returned to baseline in some patients with relapsed multiple myeloma following dosage reduction or discontinuance of bortezomib; long-term outcome of peripheral neuropathy not evaluated in patients with mantle cell lymphoma.1

Incidence of peripheral neuropathy reportedly higher in patients with relapsed multiple myeloma receiving bortezomib by IV injection compared with those receiving the drug by sub-Q injection.1 Consider sub-Q administration in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.1

Hematologic Effects

Risk of severe (grade 3 or 4) thrombocytopenia.1 Platelet count nadir typically occurs following last dose of each treatment cycle and recovers before initiation of next cycle.1 Platelet count nadir averages approximately 40% of baseline.1 Risk of GI and intracerebral hemorrhage associated with thrombocytopenia.1

Risk of severe (grade 3 or 4) neutropenia.1 Neutrophil count nadir typically occurs following last dose of each treatment cycle and recovers before initiation of next cycle.1

No evidence of cumulative thrombocytopenia or neutropenia with the treatment regimens evaluated for multiple myeloma or mantle cell lymphoma.1

Monitor platelet count prior to each dose.1 In addition, regularly monitor CBC during treatment and adjust dosage as appropriate.1 (See Dosage under Dosage and Administration.) Administer supportive care (e.g., transfusions) according to published guidelines.1

Tumor Lysis Syndrome

Tumor lysis syndrome reported.1 Increased risk in patients with large tumor burden; closely monitor such patients and take appropriate precautions.1

The manufacturer recommends temporary interruption of bortezomib therapy for assessment of reversibility of adverse hepatic effects.1 Information on results of rechallenge in these patients is limited.1 (See Hepatic Impairment under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; embryolethality and decreased fetal weight demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Specific Populations

Pregnancy

Lactation

Not known whether bortezomib is distributed into milk.1 Discontinue nursing or the drug because of potential risk to nursing infants; consider importance of drug to the woman.1

Pediatric Use

Efficacy not established in pediatric patients with relapsed pre-B acute lymphoblastic leukemia (ALL).1 In pediatric and young adult patients, the addition of bortezomib to intensive reinduction chemotherapy did not alter complete remission rates at day 36 compared with a historical control.1 No new safety concerns identified.1

Clearance (normalized to body surface area [BSA]) similar to clearance in adults.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 In clinical studies, patients ≥65 years of age with relapsed multiple myeloma had longer median time to progression, longer median duration of response, higher overall response rates, and higher incidence of grade 3 or 4 adverse effects compared with younger adults.1

Exposure may be increased in geriatric patients compared with younger adults.1 (See Geriatric Patients under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Increased exposure to bortezomib in patients with moderate or severe hepatic impairment; reduce dosage and monitor closely for adverse effects.123 (See Hepatic Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not affected by renal impairment.1 (See Renal Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Interactions for Bortezomib

Metabolized principally by CYP isoenzymes 1A2, 2C19, and 3A4; metabolism by CYP2C9 and CYP2D6 is minor.15 May inhibit CYP2C19; poor inhibitor of CYP isoenzymes 1A2, 2C9, 2D6, and 3A4.1 Does not induce CYP1A2 or CYP3A4 in vitro.1

Special Populations

Exposure increased about 60% in patients with moderate (i.e., bilirubin concentrations >1.5–3 times ULN with any AST concentrations) or severe (i.e., bilirubin concentrations >3 times ULN with any AST concentrations) hepatic impairment.123

In patients with varying degrees of renal impairment or normal renal function, exposure (based on dose-normalized AUC and peak plasma concentrations) was comparable among all the groups.1 Dialysis may decrease concentrations; administer after a dialysis procedure.1 (See Renal Impairment under Dosage and Administration.)

Mean dose-normalized peak plasma concentration and AUC of bortezomib are 25% lower in patients <65 years of age than in those ≥65 years of age.1

Compatibility

Parenteral

Solution Compatibility

Actions

Reversibly inhibits the 26S proteasome, a large protein complex that degrades ubiquitinated proteins, preventing targeted proteolysis and causing disruption of normal homeostatic mechanisms, which can lead to cell death.15

Advise women to use an effective method of contraception and to avoid breast-feeding while receiving bortezomib therapy.1 Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

Importance of informing clinician if increase in BP, bleeding, fever, constipation, or loss of appetite occurs.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

10032. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10033. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with thalidomide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10034. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with doxorubicin and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10035. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with cyclophosphamide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

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